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55 Cards in this Set
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NSAIDs (general) |
prescribed more frequently than any other class multiple therapeutic indications Are weak acids (except acetaminophen) |
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Analgesic indications only |
acetaminophen (4 hour half life) Ketorolac tromethamine (toradol, 4-6 hour) |
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Analgesic and Anti Inflammatory |
Aspirin (4 hour) Ibuprofen (motrin, advil) 4 hour naproxen (12 hour) Ketoprofen (3-4 hour) Diflunisal (12 hour) Rofecoxib/Vioxx (12-16 hour) |
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Anti- Inflammatory Indications only |
Indomethacin (4-8 hour) sulindac (12 hour) celecoxib/celebrex (12 hour)- black box warning |
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OTC NSAIDs |
Acetaminophen, Aspirin, Ibuprofen, Naproxen, Ketoprofen |
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Approved Uses for NSAIDs |
Inflammation Acute and chronic pain Fever Primary dysmenhorrea Unstable angina/post MI (aspirin only) patent ductus arteriosus in neonates (indomethacin only) |
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Prostaglandins |
Cause acute inflammation, vasodilation, Vascular permeability, fever, pain, chemotactic factors PG in every cell PG concentration high at site of inflammation Immunomodulatory response in chronic inflammation (involved in cell-cell interactions like T cell activating a B cell) Downregulates T suppressor lymphocytes Different cells contain different enzymes to make different balances of Pg (platelet mostly make thromboxanes) |
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Leukotrienes |
when lipoxygenase acts on AA cause vasoconstriction and very potent bronchoconstrictors (role in asthma) collectively called slow reacting substances of anaphylaxis
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COX (1 and 2) |
1 and 2 are isoforms- translated on separate genes 60% homology similar catabolism of AA COX 1- in all tissues, constitutive, housekeeping, inhibited by NSAIDs COX-2- Not in all tissues, inducible, expression enhanced by cytokines, upregulated at inflammatory sites (MO), inhibited by glucocorticoids and NSAIDs |
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IC50 (and aspirin) |
The lower the number, the higher the selectivity Amount to inhibit 50% A measure of potency All NSAIDs inhibit COX 1/2 with varying potencies, some have greater selectivity for Cox II Indomethicin- .1; most potent Lots of drugs are more potent than aspirin Anti inflammatory efficacy of all NSAIDs is equivalent to aspirin- so anti inflamm efficacy cannot be predicted based on relative potencies of inhibiting Cox 1 or 2 |
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Why do NSAIDs localize to inflammatory sites? |
Acidic nature and High degree protein binding in plasma (98%)- high binding promotes distribution of the drug to inflammatory site, then dissociation bc low pH Inflammatory site: increased perm, exudate volume, plasma leakage, acidic nature (causes NSAIDs to dissociate from albumin) Concentrates in inflammatory cells and synovial fluid (doesn't reach peak levels as it does in serum but prolonged stay in synovial fluid) |
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Acetaminophen (why poor anti inflammatory) |
Weak cox inhibitor weak base less than 20% bound to plasma proteins no accumulation at inflammatory site
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Celecoxib |
Weak acid Cox 2 selective sulfonamide Antibiotics also sulfonamides- allergies possible so cross reactions possible |
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NSAIDs (analgesic) vs narcotics |
Most effective against pain which accompanies inflammation Peripherally acting (narcotics are centrally acting) NSAIDs affect afferent ascending sensory to brain, work at site of pain where PG act on nociceptive receptors Opioids in descending pathways- periaqueductal grey
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Synergy |
PGE2 and bradykinin together work synergistically on pain receptors, so take ibuprofen to prevent synergy by blocking PG synthesis |
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Morphine vs Aspirin (analgesia) |
Morphine is more efficacious and quicker onset (but usually IV) 1/2 lives are similar Aspirin has analgesic ceiling (between 600-900 mg) Morphine no ceiling but side effects Tolerance to analgesic affect do not occur with NSAIDs but do occur with opioids NSAIDs not addictive or dependence liability |
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NSAID Narcotic Combo |
Analgesic is additive and raises the ceiling- bc have different mechanism for analgesia With Combos- use optimum doses of NSAIDs bc amount of analgesic activity by non narcotic is greater than narcotic when in combination |
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Thermoregulation Course of Events (infection) |
regulation in Hypothalamus, and autonomic pathways to help IL-1 goes to HT, stim release of PG and immediately increase set point for temp, HT dictates autonomic responses to retain heat (vasoconstrict, pilorection, epi, shivering) this is when the chills occur, then go to crisis and things happen so temp goes down (vasodilate, sweat) cycle takes about 4 hours
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NSAIDs (fever) |
NSAIDs decrease pyrogen induced elevation of PG in HT NSAIDs have no effect on normal temperature (exercising) Use- aspirin, acetaminophen, ibuprofen bc effective, quick onset, short half life (want to know what the infection is doing), minimal side effects |
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Reye's Syndrome |
Life threatening vomiting, lethargy, elevated liver enzymes, progressing to coma occurs often in children recovering from viral infections (flu or chicken pox) if received aspirin then higher risk than those on acetaminophen
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Primary Dysmenorrhea |
affects 50% menstruating women without pelvic disease painful menstruation, headache, diarrhea, nausea Involves PG (endometrial cell destruction releases AA, histamine, bradykinin) leading to increased uterine contractions Use ibuprofen over acetaminophen NBest are ibuprofen, naproxen, ketoprofen, diflunisal, rofecoxib |
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NSAIDs with prophylactic use: unstable angina, post- MI, without a history of MI (but at risk) |
Aspirin only 50% decrease in reoccurring MI, and incidence of first MI dose: 60-325 mg/day higher dose then lose protective effect platelet (Cox 1 only)- thromboxanes promote platelet aggregation and vasoconstriction vascular endothelium (Cox1/2)- prostacyclins- inhibit platelet aggregation and vasodilation Aspirin acetylates cox and irreversibly blocks it- platelets no nucleus so can't make more |
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Selective Cox 2 inhibitors (hemodynamics) |
Cox 2 not present in platelets; so will have opposing effects as aspirin; blocks prostacyclins and not thromboxane sytnehsis Have little effect on bleeding time |
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NSAID side effects |
Gastric: most significant Renal: much less frequency Derm: allergic responses Hematologic: aplastic anemia (but now off the market) Side effects are qualitatively the same with low and high dose Higher, chronic use then side effects occur more frequent |
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NSAID GI side effects |
10-20%- heartburn, nausea, indigestion 2-4%- massive bleed/perforated ulcer 16,000 deaths a year
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Factors associated with gastric ulcer |
established risk factors: age, preexisting ulcer, steroids/anticoagulants, high dose chronic NSAID use, type of NSAID possible risk factors: infection with H pylori, ciggys, alcy, endoscopically detected ulcers |
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Endoscopic detected ulcers |
in 1-2% of non NSAID population 50-60% of NSAID consuming poplation They are asymptomatic and heal spontaneously but only 2-4% of NSAID population develop severe GI side effects- so these are not predictors |
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Mechanism of NSAID induced ulcers |
Direct irritant effects gastric epi cells are active and concentrate NSAIDs- decrease oxidative phosphorylation and inhibit mucosal cell proliferation decreased PG synth (less bicarb so more acidic) in duodenum |
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Strategies to minimize NSAID GI effects |
NSAID formulation (buffer, coating)- did decrease endoscopic but not dangerous ulcers type of NSAID used (ibuprofen less effects, ketoprofen more effects) adjuvant therapies (H2 receptor antagonists, gel coating, methylating PGE analog to restore GI PG) GI sparing therapies |
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Misoprostol |
With methylated PGE analog (increases half life) decrease in all the ulcers |
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Sulindac |
prodrug active sulfide metabolite for GI about same as ibuprofen p450 enzymes in kidney so converted back to prodrug so no decrease in PG similar analgesic ceiling to aspirin, but slower onset bc needs conversion |
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Renal side effects |
occur less frequently Decreased renal blood flow and decreased GFR fluid retention/edema hyperkalemia Usually in patients with disease accompanied by poor renal perfusion PG made in most site of nephron- vasodilation, maintain GFR (arterioles, collecting duct) PG important in compensatory mechanism to maintain renal blood flow (CHF) so blocking this is bad |
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Guidelines to minimize nephrotoxic effects from NSAIDs |
least potent NSAID, select appropriate drug and dose to avoid accumulation determine baseline creatinine and electrolyte levels and test after therapy (check again with increase in dosage, or after adding antihypertensive/diuretic medications) weigh themselves daily (water retention) |
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NSAID hypersenstivity |
10-20% in asthmatics 1-2% in general minutes-hours after ingestion No immunological mechanism involved All NSAIDs CROSS REACT resembles allergy (can use acetaminophen if are hypersensitive) Shunt theory- asthmatics have more COX activity in lungs, so more leukotrienes (SRSA) and bronchoconstriction |
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NSAID in pregnancy |
most contraindicated throughout use in third trimester: risk hemorrhage at delivery, decrease uterine contractions, premature closure of fetal ductus arterioses No evidence of teratogenicity in humans |
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Pharmakokinetic interactions |
Related to protein binding- can boot off other protein binding drugs (narrow therapeutic range- so it depends on drug being displaced ie penicliin then no problem) Worry about coumarin anticoagulants, phenytoin, tolbutamide, methotrexate relatively safe bc increased free drug means increased availability for metab/excretion reach new steady state quickly |
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Pharmacodynamic Interactions |
Worry about antihypertensives- beta blockers, diuretics Anticoagulants Due to bleeding effects |
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Salicylates |
aspirin Diflunisal
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Diflunisal |
Higher analgesic ceiling and longer half life than aspirin Similar ceiling to acetaminophen/codeine |
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Aspirin (preparations) |
Many different aspirin preparations that have varied absorption rates But no diff in analgesic efficacy
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Aspirin metabolism at low dose |
First Order Kinetics aspirin half life is 20 min but deacetylation by plasma and gastric enterases to salicylate ion (half life 4 hours)- then 80% conjugated by liver, 10% hydroxylated in liver and 10% excretion in kidney salicylate ion is active (aspirin too) |
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Aspirin high dose metab(get excretion faster by) |
Zero order kinetics liver saturates Can't saturate gastric/plasma enterases now kidney excretion is primary mode so half life can go up to 12 hours when taken over normal therapeutic dose range Can alkalyze the urine and this increases excretion- only works for aspirin to lower blood levels bc the others are mainly metabolized by liver (so other NSAIDs do NOT show zero order kinetics)
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aspirin poisoning level and symptoms |
more than 30 mg/100 mL CNS effects first (increased respiration/resp alkalosis) then come... uncoupling oxidative phosphorylation (decrease ATP, increase heat production so paradoxical fever) then come... fat/carb metabolism (increased ketones, metabolic acidosis) then comes.... electorlyte imbalance (convulsions, CV collapse, coma)
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drugs that are high levels of parent drugs excreted by kidney |
ketorolac- 40% unchanged in urine, not much metabolized by liver indomethacin- 30% More likely to produce renal failure |
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More ikely to damage the liver (2 rules) |
greater potency for COX higher concentrations of parent drug excreted by kidney |
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Acetaminophen (liver damage) |
NAPQI: reacts with sulfhydryl groups on liver mb and produces liver necrosis Therapeutic dose is detoxified by hepatic glutathione S transferases P450 enzymes form NAPQI dose is about 10 grams for this antidote: N acetyl cysteine- provides extra sulfhydryl group |
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Acetaminophen overdose |
Minor immediate complaints (unlike aspirin) few signs of liver damage for 2-3 days serum transaminases elevated (alanine aminotransferase ALT) 30-40% had 3X normal Liver necrosis develops and is irreversible |
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Factors increasing susceptibility to acetaminophen induced liver toxicity |
P450 inducers (phenytoin) fasting or protein deficient diets Pregnancy alcohol children (dehydration, diet) |
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Acetaminophen safe alternative to aspirin as analgesic/antipyretic in these people |
children pregnant women asthmatics gout bleeding disorders diseases accompanied with renal deficiency |
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Propionic acids |
ibuprofen ketoprofen naproxen fenoprofen flurbiprofen oxaprozin Have higher analgesic ceiling compared to ASA: ibuprofen like aspirin/codeine |
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naproxen (analgesia) |
higher ceiling than aspirin longer half life (12 hours) aleve |
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Acetic acids |
indomethacin sulindac ketorolac (only analgesia)
All used for anti inflammatory except ketorolac |
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Indomethacin |
very potent but not very get analgesic ceiling so only antiinflammatory indication |
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ketorolac (toradol) |
analgesic efficacy of IM is comparable to 12 mg morphine! not for anti inflammatory Doesn't depress respiration But oral administration has analgesic ceiling similar to ibuprofen
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Cox 2 inhibitors |
similar analgesic efficacy as nsaids not proven to have less adverse side effects CV toxicities occur celebrex: first to make a billion (celecoxib) vioxx: rofecoxib |
